Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle
Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle
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DOI：
10.1016/j.molcel.2005.05.011
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发表时间：
2005-06-10
期刊：
影响因子：
16
通讯作者：
Desiderio, S
中科院分区：
文献类型：
--
作者：
Jiang, H;Chang, FC;Desiderio, S
rag2在G1到s过渡阶段的周期性破坏将V(D)J重组偶联到G0和G1细胞周期阶段，并协调rag2介导的DNA切割和非同源末端连接的DNA修复。为了确定这种情况发生的机制，我们在无细胞系统中复制了V(D)J重组酶的细胞周期依赖调控。在体内，泛素-蛋白酶体途径在S期细胞裂解物和S期进行RAG-2的破坏。值得注意的是，Skp2-SCF泛素连接酶通过破坏p27在细胞周期调节中发挥核心作用，在体外介导RAG-2的泛素化和体内RAG-2的降解。Skp2-SCF对抗原受体基因组装的调控提供了DNA重组与细胞周期之间意想不到的直接机制联系。
The periodic destruction of RAG-2 at the G1-to-S transition couples V(D)J recombination to the G0 and G1 cell cycle phases and coordinates RAG-mediated DNA cleavage with DNA repair by nonhomologous end joining. To define the mechanism by which this occurs, we reproduced cell cycle-dependent regulation of the V(D)J recombinase in a cell-free system. The ubiquitin-proteasomal pathway carries out destruction of RAG-2 in lysates of S phase cells and during S phase in vivo. Remarkably, the Skp2-SCF ubiquitin ligase, which plays a central role in cell cycle regulation through the destruction of p27, mediates ubiquitylation of RAG-2 in vitro and degradation of RAG-2 in vivo. The regulation of antigen receptor gene assembly by Skp2-SCF provides an unexpected and direct mechanistic link between DNA recombination and the cell cycle.